The KRAS-variant is a biologically functional, microRNA binding site variant in the KRAS oncogene, which predicts increased cancer risk especially for women. MicroRNA (miRNA) binding site variants in the 3′ untranslated region (3′UTR) of important growth and survival genes are a recently discovered novel class of germ-line mutations, which are powerful biomarkers of cancer risk and treatment response (Cipollini et al. (2014) PHARMACOGENETICS AND PERSONALIZED MEDICINE 7:173-191).
One of the first mutations discovered in this class is the KRAS-variant, a let-7 binding site mutation in the 3′UTR of the KRAS oncogene (Chin et al. (2008) CANCER RES 68:8535-40). This mutation predicts an increased risk of several cancers, including non-small cell lung cancer (Id.), triple negative breast cancer (TNBC) in premenopausal women (Paranjape et al. (2011) THE LANCET ONCOLOGY 12(4):377-386) and ovarian cancer (Ratner et al. (2010) CANCER RESEARCH 15:6509-15; Ratner et al. (2012) ONCOGENE 31(42):4559-66; Pilarski et al. (2012) PLOS ONE 7(5):e37891). The KRAS-variant has also been shown to predict unique tumor biology, with tumors in KRAS-variant patients exhibiting a KRAS-addicted signature as well as an estrogen-negative, basal-like gene expression pattern (Ratner, 2012, supra; Paranjape, supra). Women with the KRAS-variant have also been found to be at a significantly increased risk of developing multiple primary cancers, including breast and ovarian cancer, as well as a third independent cancer in the same individual (Pilarski, supra).
Women with the KRAS-variant are also at a significantly increased risk of developing multiple primary cancers, including breast and ovarian cancer, as well as a third independent cancer in their lifetime (Pilarski, supra). Multiple primary cancer, although difficult to predict, is not rare, as up to one in eight cancer patients will be diagnosed with a new primary cancer after their first cancer diagnosis (metachronous cancer), and one in forty patients will be diagnosed with two cancers at the same time (synchronous cancer) (Levi et al. (2014) EUR J CANCER PREV doi: 10.1097/CEJ.0000000000000085). While it is hypothesized that metachronous cancers may be caused by primary cancer treatment, it is also thought that genetics plays a significant role in the development of both synchronous and metachronous cancers (Bhatia (2014) CANCER. doi: 10.1002/cncr.29096; Amer (2014) CANCER MANAG RES 5:119-34). Multiple primary breast cancer (MPBC) is one of the most common forms of multiple primary cancer (Howe et al. (2005) BREAST CANCER RES TREAT 90(3):223-232), yet it remains difficult to identify those at risk. Currently identified risk factors for the development of multiple or bilateral primary breast cancers include young age at first diagnosis (Raymond et al. (2006) BRITISH JOURNAL OF CANCER 94(11):1745-1750; Marcu et al. (2014) EUROPEAN JOURNAL OF CANCER CARE 23(1):51-64; Kurian et al. (2009) JOURNAL OF THE NATIONAL CANCER INSTITUTE 101(15):1058-1065); first BC of lobular histology (Howe, supra; Chen et al. (1999) CANCER EPIDEMIOL BIOMARKERS PREV 8(10):855-61; Narod (2014) NATURE REVIEWS CLINICAL ONCOLOGY 11(3):157-166); high BMI (>30) in pre-menopausal patients with a hormone-receptor negative first primary (Brooks et al. (2012) BREAST CANCER RES TREAT 131(2):571-580); positive family history of breast cancer (Reiner et al. (2013) JOURNAL OF CLINICAL ONCOLOGY 31(4):433-439); and mutations in BRCA 1, BRCA 2 (Malone et al. (2010) JOURNAL OF CLINICAL ONCOLOGY 28(14):2404-2410; Metcalfe et al. (2011) BRITISH JOURNAL OF CANCER 104(9):1384-1392) or CHEK 2 (Broeks et al. (2004) BREAST CANCER RES TREAT 83(1):91-3). Additionally, in a small case series, the KRAS-variant was found in 57.1% of uninformative (BRCA negative) patients who developed bilateral breast cancer and ovarian cancer (Pilarski, supra). Factors decreasing multiple primary breast cancer risk have also been identified, and include menarche after 13 years of age, multiparity (Narod, supra), treatment with anti-hormonal agents or chemotherapy (Clarke et al. (2005) LANCET 365(9472):1687-717; Alkner et al. (2009) EUR J CANCER 45(14):2496-502) and prophylactic surgical intervention (Metcalfe, supra; Lostumbo et al. (2004) COCHRANE DATABASE SYST REV (4):Cd002748). These findings indicate that second BC risk can be impacted by estrogen alterations either before or after the first BC diagnosis.
Evidence that estrogen exposure increases primary breast cancer risk includes increased BC risk in women experiencing early menarche, late menopause, obesity, nulliparity or advanced maternal age at first birth (Anderson et al. (2014) BREAST CANCER RESEARCH AND TREATMENT 144(1):1-10). In addition, in vitro studies using the breast epithelial line MCF10A support the hypothesis that excess estrogen and its metabolites can lead to increased transformation, or breast cancer initiation (Liu et al. (2004) BREAST JOURNAL 10(6):514-521; Wang et al. (2013) ONCOGENE 32(44):5233-5240). However, it appears that estrogen is not a risk for breast cancer for all women, as has come to light through data surrounding hormone replacement therapy use (HRT) (Beral (2003) LANCET 362(9382):419-427; Chlebowski et al. (2013) JOURNAL OF THE NATIONAL CANCER INSTITUTE 105(8):526-535). Initially, the Million Women Study and Women's Health Initiative reported that current and/or prolonged use of HRT correlated with an increased risk of breast cancer. Because these tumors tended to be lower grade, with over-representation of lobular or tubular subtypes compared to other ductal cancers (Calle et al. (2009) CANCER 115(5):936-45), it was hypothesized that HRT was causing cancers that otherwise would not have arisen. However, a follow-up WHI report found that there was actually no increased breast cancer risk for patients assigned to estrogen-only preparations compared to placebo (Anderson et al. (2004) JAMA 291(14):1701-12). In fact, after a median follow up of 11.8 years (IQR 9.1-12.9), post-menopausal use of estrogen alone was associated with a lower breast cancer incidence than placebo (HR 0.77 (CI 0.62-0.95, p 0.02)) (Id.).
For women with the KRAS-variant, there is growing evidence that estrogen may differentially impact their overall cancer risk and tumor biology. This includes: a higher risk of non-small cell lung cancer for women versus men with the KRAS-variant (unpublished data); ovarian cancer risk almost exclusively in post-menopausal women with the KRAS-variant (Pilarski, supra); in increased risk of estrogen receptor (ER) negative tumor development in KRAS-variant patients (TNBC (Paranj ape, supra) and type II uterine cancer (Lee et al. (2014) PLOS ONE, 9(4):e94167), and; evidence that KRAS-variant post-menopausal breast cancer patients with a history of HRT are significantly more likely to develop biologically aggressive breast cancer (Cerne et al. (2012) BMC CANCER 12(105)). These findings suggest that estrogen alterations may differentially impact the KRAS-variant, and, there is in fact strong evidence that such miRNA binding site mutations are “influenced” by external exposure (Salzman et al. (2011) NAT MED 17:934-5). This is believed to be through alterations in miRNAs, which are the immediate responders to cellular stress, and which directly act through the 3′UTR sites affected by these mutations (Id.).
Substantial evidence that the KRAS-variant acts as a cancer biomarker of response to therapy also exists. This includes cisplatin resistance in KRAS-variant patients with ovarian or head and neck cancer (Rather, 2012, supra; Chung et al. (2014) ANN ONCOL, July 31. [Epub ahead of printing]), cetuximab sensitivity in KRAS-variant patients with colon cancer (Saridaki et al. (2014) CLIN CANCER RES 20(17):4499-510) or head and neck cancer (Chung, supra), and erlotonib resistance but sorafenib sensitivity in KRAS-variant patients with non-small cell lung cancer (NSCLC) (Weidhaas et al. (2014) J CLIN ONCOL 32(52):suppl; abstr 8135). Cell line data further supports the unique response of the KRAS-variant to chemotherapy exposures (Saridaki, supra).
Accordingly, there is a need in the art for methods to prevent and treat cancer in subjects with KRAS-variant. In addition, there is a need in the art for methods to predict who is at risk for the development of second primary breast tumors, so that preventative measures can be taken and treatment appropriately administered.